Clinical studies have found that the combined therapy with hydroxychloroquine and azithromycin is effective for COVID-19 infection. The combination acts as an antiviral therapy against SARS-CoV-2 and prevents bacterial super-infections during viral laods. Addition of azithromycin to hydroxychloroquine was found to be significantly more efficient for virus elimination.¹

Pharmacological Class: Anti-malarial and Antibiotic

Combination: WHO supports consideration of hydroxychloroquine for reducing the post-exposure prophylaxis and longer-term prophylactic use in COVID-19 infection.² Azithromycin has been found to reinforce the effect of hydroxychloroquine in SARS CoV-2 patients. It also prevents severe respiratory tract infections.¹ However; more clinical trials with large sample size are needed to confirm the efficacy and safety of the combination.

Monotherapy:

• Hydrooxychloroquine: Acute malarial attack caused by Plasmodium vivax, P. malariae, P. ovale, and susceptible strains of P. falciparum⁴

• Azithromycin: Acute bacterial exacerbations of chronic obstructive pulmonary disease, acute bacterial sinusitis, acute otitis media , community-acquired pneumonia⁵

The anti-viral effect of hydroxychloroquine can be attributed to its ability to inhibit the binding efficiency between ACE-2 receptors on host cells and the spike protein on the surface of corona virus, through which progression of the disease from mild to severe might be attenuated.⁶ Azithromycin acts synergistically with hydroxychloroquine and also has been found to be active against Zika and Ebola viruses. Azithromycin also prevent severe respiratory tract infections when administrated to patients suffering viral infection. ¹

Dosage as per clinical study on SARS-CoV-2 patients¹

• Hydroxychloroquine sulfate 600 mg daily for 5 days
• Azithromycin 500 mg on day1 followed by 250 mg per day, the next four days

*As per WHO, the dosage and treatment schedules for hydroxychloroquine that are currently under consideration do not reflect those used for treating patients with malaria. The ingestion of high doses of hydroxychloroquine may be associated with adverse or seriously adverse health outcomes.³

Recommended dosage for treating Malaria⁴

• Hydroxychloroquine sulfate 800 mg (620 mg base) followed by 400 mg (310 mg base) at 6 hours, 24 hours and 48 hours after the initial dose (total 2000 mg hydroxychloroquine sulfate or 1550 mg base)

Recommended dosage for treating Bacterial infections⁵

• Community-acquired pneumonia (mild severity): Azithromycin 500 mg as a single dose on Day 1, followed by 250 mg once daily on Days 2 through 5.
• Acute bacterial exacerbations of chronic obstructive pulmonary disease (mild to moderate): Azithromycin 500 mg QD x 3 days OR 500 mg as a single dose on Day 1, followed by 250 mg once daily on Days 2 through 5.
• Acute bacterial sinusitis: Azithromycin 500 mg QD x 3 days
• Acute otitis media: 30 mg/kg as single dose or 10 mg/kg once daily for 3 days or 10 mg/kg as single dose on first day followed by 5 mg/kg/day on Days 2 through 5

Hydroxychloroquine has variable bioavailability of approximately 74%, it has complex and extensive metabolism. The plasma half-life increases proportionally with increasing dose. The main route of excretion is renal, with 23-25% of the excreted compound in its unmodified form, along with the metabolites.⁷

The oral absolute bioavailability of azithromycin 250 mg is approximately 38%. It is widely distributed throughout the body and has terminal elimination half-life of 68 hours which is due to extensive update and subsequent release of drug from the tissues.5

Contraindicated in

• patients with known allergy to hydroxychloroquine, chloroquine, azithromycin, erythromycin, any macrolide or ketolide antibiotic
• patients with retinopathy, G6PD deficiency and QT prolongation
• patients with a history of cholestatic jaundice/hepatic dysfunction associated with prior use of azithromycin
• breastfeeding and pregnant women 

• Digoxin: It may increase serum digoxin levels. Serum digoxin levels should be closely monitored in patients receiving combined therapy
• Drugs that prolong QT interval and other arrhythmogenic drugs: Hydroxychloroquine prolongs QT interval and should not be administered with other drugs that have the potential to induce cardiac arrhythmias.
• Insulin or antidiabetic drugs: Hydroxychloroquine may enhance the effects of a hypoglycemic treatment.
• Antiepileptics: The activity of antiepileptic drugs might be impaired if co-administered with hydroxychloroquine
• Nelfinavir: Close monitoring for known adverse reactions of azithromycin, such as liver enzyme abnormalities and hearing impairment is warranted
• Warfarin: Use with azithromycin may increase coagulation times; monitor prothrombin time

Common;

• Headache
• Dizziness
• Diarrhea
• Abdominal pain
• Stomach cramps
• Vomiting

Uncommon:

• Blurred vision or other vision changes
• Ringing in your ears or hearing loss
• Angioedema
• Hives
• Sore throat
• Severe hypoglycemia
• Cholestatic Jaundice
• Vaginitis
• Nephritis

Very rare:

• Heart disease including heart failure
• Unusual bleeding or bruising
• Muscle weakness
• Hair loss
• Abnormal mood changes and suicidal thoughts
• Kidney failure
• Multiple organ failure

Should be used with caution in

• patients having glucose-6-phosphate dehydrogenase (G-6-PD) deficiency
• nursing and pregnant women
• patients with gastrointestinal, neurological, or blood disorders, and in those with a sensitivity to quinine
• patients with hepatic disease or alcoholism or in conjunction with known hepatotoxic drugs

A recent study evaluated the role of hydroxychloroquine and azithromycin on respiratory viral loads in Chinese Covid-19 patients. Out of 36 inclduded patients, 6 patients were asymptomatic, 22 had upper respiratory tract infection symptoms and eight had lower respiratory tract infection symptoms. The patients were administered with hydroxychloroquine 600 mg daily for 5 days and azithromycin 500 mg on day 1 followed by 250 mg through day 5. The study results showed a significant reduction of the viral carriage at day 6-post inclusion in most of the patients which indicate that hydroxychloroquine and azithromycin treatment is significantly associated with viral load reduction/disappearance in Coronavirus infected patients.¹

1. International Journal of Antimicrobial Agents 2020 March 20: 105949
2. WHO Blue print COVID-1Informal consultation on the potential role of chloroquine in the clinical management of COVID 19 infection available through link https://www.who.int/blueprint/priority-diseases/key-action/RD-Blueprint-expert-group-on-CQ-call-Mar-13-2020.pdf?ua=1
3. WHO Malaria and the COVID-19 pandemic 27 March 2020 available through link: https://www.who.int/news-room/q-a-detail/malaria-and-the-covid-19-pandemic
4. FDA reference id 4047416
5. FDA reference id 4051690
6. Journal of Antimicrobial Chemotherapy, dkaa114,  https://doi.org/10.1093/jac/dkaa114
7. IOSR Journal Of Pharmacy Volume 4, Issue 11 (November 2014), PP. 53-64